Actinomycin D is a known anticancer drug whose mode of action is well characterized. In addition, the molecular structure of its complex with the receptor molecule (DNA) is known. This represents a unique opportunity to attempt a rational design of new drugs that might be more effective or less toxic. After careful examination of Sobell's intercalation model for the actinomycin D-DNA complex, we have proposed two strategies for synthetic modifications of actinomycin: (1) radical alteration of the chromophore while retaining the peptides unchanged, and (2) substitution of unnatural hydrophobic amino acids in the peptide rings without changing the chromophore. Strategy (1) requires synthesis of the cyclic pentapeptide before attachment to the chromophore. We have isolated and characterized a blocked linear pentapeptide which should be suitable for deblocking and cyclization. The interaction of actinomycin analogs with DNA and dinucleotides is being studied in detail using spectroscopic, hydrodynamic and biochemical methods to determine similarities and differences between them and actinomycin D. These data, along with in vivo test results, will be used to evaluate the success of the drug design strategies and the underlying rationale, and will contribute to a better understanding of the mode of action of actinomycin D.